This invention relates to novel urethane-containing aminosteroid compounds. This invention also relates to pharmaceutical compositions containing these novel compounds as well as to a method of treating Congestive Heart Failure (CHF) using the compounds of the present invention.
CHF is a progressive disease wherein the heart is increasingly unable to supply adequate cardiac output (CO), which is the volume of blood pumped by the heart over time, to deliver the oxygenated blood to the peripheral tissues. When the heart initially fails, the rest of the body compensates for the loss in CO and such compensatory mechanisms eventually result in the syndrome known as CHF. As CHF progresses, structural and hemodynamic damages occur. Such structural damage manifests itself macroscopically as ventricular hypertrophy in the myocardium, and microscopically as interstitial, perivascular and replacement fibrosis in the ventricle wall, decreased myocardial capillary density, and myocardial cell death. When fibrosis of the myocardial tissue occurs it compromises the functioning of the heart because the remaining viable myocardial cells have a greater workload.
Hemodynamically, in the failing heart, the capacity to develop force during systole (the phase in the cardiac cycle during which ejection of blood from the ventricles occurs) is reduced. Thus, a greater end-diastolic volume (during the diastolic phase of the cardiac cycle filling of the ventricles occurs) is needed to perform any given level of external work. In cardiac failure, reduced ejection, caused by a mismatch of work capacity and load, results in an increase in end diastolic pressure and pulmonary capillary pressure. Pulmonary congestion and peripheral edema often follow. From the patient's perspective, as CHF progresses, the patient experiences increasingly worsening symptoms of fatigue and dyspnea.
Effective treatment of CHF requires a determination of its etiology, if possible, because some CHF etiologies have their own unique form of treatment. CHF has a variety of etiologies, including diseases of the myocardium such as coronary artery disease or myocarditis; diseases of the valves, such as mitral valve prolapse or aortic stenosis; pericardial diseases; congenital heart disease; pulmonary disease, cardiac arrhythmias, hypertension, and diabetes. For example, if the etiology of CHF is myocarditis or an arrhythmia, then treating the patient with an antimicrobial or an anti-arrhythmic agent, respectively, may restore the patient to normal cardiac function.
However, once the etiologies not responding to other treatments have been ruled out, treatment by one or more of three modalities is initiated: 1) improvement of the heart's pumping capacity by administration of an inotropic agent, such as digitalis, 2) reduction of the heart's workload by rest and/or by administration of vasodilators such as captopril, and 3) controlling sodium and water retention by a low sodium diet or administration of a diuretic such as thiazide. Treatment of CHF is individualized according to the patients symptomatology and tolerance for certain medications. For example, some patients may have a strong tendency to develop digitalis toxicity, while other patients with mild symptoms may benefit from diuretics which have a greater therapeutic index. Moreover, current wisdom suggests that diuretics are appropriate first line CHF therapy and that diuretic treatment should be followed by vasodilators and digitalis. It has also been noted that digitalis is most effective in patients suffering from severe CHF. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E. K., Quick Reference to Cardio-vascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N. O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976).
While digitalis is useful for ameliorating the symptoms associated with the hemodynamic problems characteristic of severe CHF, its low therapeutic index, in effect, limits its therapeutic utility. See generally, Braunwald, Heart Disease: A Textbook of Cardiovascular Medicine, Vol. (3rd ed. 1988), Chung, E. K., Quick Reference to Cardiovascular Disease, Chapter 27 (2d ed. 1983) and Fowler, N. O., Cardiac Diagnosis and Treatment, Chapter 12 (2d ed. 1976) and Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chapter 34 (8th ed., 1990).
The toxicity problems associated with digitalis has prompted investigators to attempt to develop safer cardioactive compounds. Cardioactive steroid nucleus containing compounds have been described in the following patents: World Patent Publication WO 07/0416787/04167 to Chiodini, et al. published Jul. 16, 1987 describes aminoglycoside steroid derivatives substituted by an amino-sugar residue at the 3-position and an acetal linkage at the 14-position. The disclosure states that the compounds are useful for the treatment of hypertension. French Patent 2,642,973 of Guina published Aug. 17, 1990 describes a digitalis-like compound, 2,3-dioxymethyl-6-methyl-3-beta-D-glucose-strophanthidine, which contains the steroid nucleus substituted at the 3-position with a glucose moiety and at the 17-position with the lactone moiety, and at the 14-position with a hydroxyl group. The disclosure states that the compound is useful in preventing pathologic states resulting from cardiac insufficiencies for which digitalis is prescribed and for preventing pathologic states resulting from hypertension due to arterial calcification. The Guina compound is also alleged to be a positive inotrope, a peripheral vasodilator, and an anti-arrhythmic agent. World Patent Publication WO 87/04168 to Chiodini et al. published Jul. 16, 1987 discloses an aminoglycoside steroid having an alkyl substituted amino sugar at the 3-position, such as 2-amino or 2-alkylamino-2-deoxy-hexopyranosyl, 3-amino or 3-alkylamino-3-deoxy-hexo-pyranosyl, 3-amino or 3-alkyl-amino-3,6-dideoxy-hexopyranosyl, 3 amino or 3-alkylamino-2,3,6-trideoxy-hexopyranosy 4-amino or 4-alkylamino 2,4,6-trideoxy-hexopyranosyl residues, and a cyclic amide (lactam) at the 17-position. The 14-position is substituted with a H. The compound is said to be useful as an antihypertensive. World Patent Publication WO 91/17176 to Kenny, et al. published Nov. 14, 1991 discloses a steroid glycoside useful as a pressor agent, having a sugar moiety at the 3-position; such as a pentose, hexose or combinations thereof, and a lactone ring at the 17-position; the 14-position is substituted with an OH, H or a F, Cl, Br or NH.sub.2 ; and DD 296,502 A5 to Siemann, et al. granted Dec. 5, 1991 discloses a steroid amide for treating cardial insufficiency wherein the 3-position is substituted with a sulphonyl amino group and the 17-position is substituted with a 5 or 6-membered lactone ring; the 14-position is substituted with an OH. U.S. Pat. No. 5,144,017 to LaBella, Sep. 1, 1992 discloses steroid compounds said to be useful as cardiac stimulants wherein the 3-position is substituted with a glycoside radical such as .beta.-D-glucoside, .alpha.-L-rhamnoside, tridigitoxoside and the 17-position is substituted with an acetoxy group, or an amino group; and the 14-position has an OH group; and U.S. Pat. No. 5,175,281 to McCall, Dec. 29, 1992 discloses pyrimidinylpiperazinyl steroid compounds useful in treating spinal trauma, head injury and the subsequent cerebral vasospasm, preventing damage following cardiopulmonary resuscitation and cardiac infarction wherein the 3-position is OH, CH.sub.3 O, COOH, or benzoxy the 14-position is a H and the 17-position is a heterocyclic amine. DD 256,134 A1 to Wunderwald, et al., granted Apr. 27, 1988 discloses a process for making cardioactive steroids wherein the 3-position of the steroid molecule is substituted with a morpholinoformyloxy residue, and the 17-position of the steroid molecule is substituted with a lactone ring; and the 14-position is substituted with OH, H or an olefin. Said compounds are alleged to be useful for increasing cardiac contractility. JP 4-290899 to Ichikawa, et al., laid open Oct. 15, 1992, discloses a cardiotonic steroid compound wherein the 3-position of the steroid nucleus is substituted with an oligosaccharide; wherein further said oligosaccharide consists of three glucopyranosyl moieties and the 14-position is substituted with an OH group; and the 17-position is substituted with a lactone ring. Templeton, et al., 36 J. Med. Chem. 42-45 (1993) disclose the synthesis of derivatives of 14-hydroxy-21-nor-5.beta., 14.beta.-pregnane and 5.beta.,14.beta.-pregnane C-3.alpha.-L-rhamnosides and tris-.beta.-D-digitoxosides. Said compounds are reported to be effective cardiotonics. These derivatives, possessing a C-17.beta.COCH.sub.2 OH, CH.sub.2 OH, CO.sub.2 OH, CO.sub.2 Me, CH.sub.2 NH.sub.2, or CH.sub.2 NO.sub.2 group, bind to the digitalis receptor recognition site of heart muscle. Templeton, et al., J. Chem. Sci. Perkin. Trans., 2503-2517 (1992) disclose the synthesis of 20.alpha.- and 20.beta.-acetamido-, amino-, nitro- and hydroxy-3.beta.-glycoside (.alpha.-L-rhamnopyranoside and tris-.beta.-D-digitoxo-side) and genin derivatives of 14-hydroxy-5.beta.,14.beta.-pregnane together with the C-20 oxime, hydrazone and amidinohydrazone. These compounds are asserted to be effective cardiotonics. Adeoti, S. B., et al., 12 Tetrahedron Letters, 3717-3730 (1989) disclose a method for introducing a 14.beta.-amino function into a steroid molecule. Said method allows for the preparation of the cardioactive 14.beta.-amino-5.beta.-pregnane-3.beta., 20.beta.diol.
Additionally, angiotensin converting enzyme inhibitors (ACEI) have been shown to reduce mortality in CHF patients. See Nicklas, J. M. and Pitt, B., et al. (The SOLVD Investigators), "Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure", N. Engl. J. Med. 325(5):293 (1991).
Nevertheless, four million people still suffer from CHF. The five year mortality after diagnosis of CHF is 60% for men and 45% for women. This is a clear indication that better therapies directed toward treating CHF are needed. See Parmley, W. W., "Pathophysiology and Current Therapy of Congestive Heart Failure", J. Am. Col. Cardiol. 13:771-785 (1989); Francis, G. S. et al., "Congestive Heart Failure: Pathophysiology and Therapy,"Cardiovascular Pharmacology, 3rd Edition (1990).
The 14-aminosteroid compounds have been shown to be useful in treating CHF by increasing cardiac contractility. These compounds provide the therapeutic benefit of increased cardiac contractility without the side effects of digitalis. These 14-aminosteroids are described in the following three patents, all incorporated by reference herein: U.S. Pat. No. 4,552,868, Jarreau, et al., issued Nov. 12, 1985; U.S. Pat. No. 4,584,289 Jarreau, et al., issued Apr. 22, 1986 and U.S. Pat. No. 4,885,280 Jarreau, et al., issued Dec. 5, 1989. These three patents describe 14-aminosteroid compounds possessing positive inotropic activity. It has now been discovered that the urethane-containing aminosteroid compounds of the present invention wherein the 3-position is substituted with a urethane-containing moiety are more effective inotropes. Said urethane-containing aminosteroids are more resistant to metabolism and therefore provide a longer duration of inotropic activity than the prior art 14-aminosteroids.